1. Field of the Invention
This invention concerns liposomes, and more particularly liposomal delivery systems for transporting materials such as drugs, nucleic acids, and proteins. The liposomes selectively release their contents in response to an external triggering event, such as photoillumination.
2. General Discussion of the Background
Liposomes are microscopic lipid bilayer vesicles that enclose a cavity. The liposomal vesicles can contain a single bilayer (unilamellar vesicle) or multiple bilayers (multilamellar vesicle). These vesicles can encapsulate water-soluble drugs in their aqueous cavities, or carry lipid soluble drugs within the membrane itself. Liposomes have already been used for encapsulating therapeutic agents, such as cytotoxic drugs, and carrying them to biological target sites. For example, U.S. Pat. No. 3,993,754 discloses an improved chemotherapy method for treating malignant tumors in which an antitumor drug is encapsulated within liposomes and the liposomes are injected into an animal.
Encapsulation of pharmaceuticals in liposomes can reduce drug side effects, improve pharmacokinetics of delivery to a target site, and improve the therapeutic index of a drug. A serious limitation to the widespread use of liposomes, however, has been the difficulty of directing them to specific target sites. Liposomes administered intravenously to subjects are rapidly accumulated in the reticuloendothelial system. High liposome concentrations are thereby rapidly achieved in organs with fenestrated capillaries, such as the liver, spleen, and bone marrow. Liposomal systems can be effective in treating tumors that infiltrate these organs (such as hematologic malignancies), but have been less useful in treating targeted tumors in other anatomical locations. Previous research has investigated ways to "trigger" release from liposomes at other than reticuloendothelial target sites.
One prior approach has promoted leakage of liposome contents by heating a liposomal saturated target site above a critical temperature range, for example by radio frequency heating of target tissues. Yatvin et al., Science 202:1290 (1978). Another approach has used liposomes prepared from pH sensitive lipids, which leak their pharmaceutical contents into low pH target regions. Such areas of localized acidity are sometimes found in tumors, hence it has been proposed that intravenous administration of such liposomes would preferably selectively release anti-cancer chemotherapeutic agents at target tumors. Yatvin et al., Science 210:1253 (1980).
U.S. Pat. No. 4,882,164 similarly discloses a light sensitive liposome which undergoes a trans to cis isomerization upon irradiation with an appropriate wavelength of light (ultraviolet light) to allow the fluid contents of the liposome to escape through the membrane into the surrounding environment. Finally, GB Patent 2,209,468 discloses liposomes with an incorporated photosensitizing agent that absorbs light and alters the lipid membrane to release a drug from the liposome. Several reports of vesicle contents release using UV or visible light have appeared, but none of these systems have used biologically compatible lipids that are disrupted by light frequencies having tissue penetration depths exceeding 1 mm.
Photodynamic therapy (PDT) is another approach to treating localized areas of diseased tissue. A photosensitizer drug is administered systemically, topically, or by injection into a target site, such as a tumor. Illumination of the target site by an appropriate light source, such as an argon-pumped dye laser or sunlamp, induces a cytotoxic effect on the cells of the target site by one of two proposed mechanisms. In Type I photosensitization, the electronically excited drug reacts directly with a biological substrate, forming radicals which can initiate subsequent radical reactions that induce cytotoxic damage. Type II photosensitization involves energy transfer from the electronically excited drugs to oxygen, producing singlet molecular oxygen which subsequently produces cytotoxic oxygenated products.
Photodynamic therapy (PDT) has been used experimentally in cancer patients, and thousands of clinical trials are in progress throughout the world. One experimental drug known as Photofrin II (a purified version of hematoporphyrin derivative) is currently involved in randomized clinical trials. Other photosensitizing drugs used in photodynamic therapy procedures include phthalocyanines, merocyanine 540, substituted purines, xanthenes (Rhodamine 123 6G&B), cationic cyanine dyes, chlorine polymers, chalcogenapyrylium dyes containing selenium or tellurium atoms in the chromophore, phenothiazinium derivatives, benzophenoxoniums (Nile Blue A) and triarylmethanes (Victoria Blue BO [VB-BO]). Although remarkable results have been obtained in some PDT trials, several problems remain. Very high systemic doses of the sensitizer must often be given to achieve therapeutic levels at irradiated tumor sites, hence many sites in the body are nonselectively infiltrated by the sensitizer. The low solubility of some of the sensitizers reduces their usefulness for systemic administration because intravascular administration can provoke thromboembolic events.
Accordingly, it is an object of the present invention to provide an improved liposomal drug delivery system that is biocompatible and capable of triggered release of its contents.
Yet another object is to provide an improved liposome suitable for triggered release of its contents in response to alterations of pH.
Another object is to provide an improved liposomal triggered release system that reduces the effect of the triggering event on the drug carried by the liposome.
Yet another object is to provide an improved liposome suitable for use in photodynamic therapy.
Finally, it is an object of this invention to provide an improved method of photodynamic therapy which overcomes solubility problems with sensitizer drugs and is capable of delivering the drugs more selectively to a target site.